This grant application is written in response to RFA-AA-07-015 "Mechanisms of Nervous System Dysfunction: Impact of Alcohol Abuse on HIV-Neuropathogenesis (R01)," the stated intent of which is "to encourage applications that will determine the effects of abusive alcohol consumption on the abilities of viral encoded proteins and/or host factors to cause the neuronal dysfunction and damage that produces HIV-associated neurological complications" including painful "antiretroviral toxic neuropathy (ATN) that results from neurotoxicity caused by antiretroviral therapy." Alcohol abuse is one of the most important comorbid risk factors for peripheral neuropathy in patients receiving therapy for HIV/AIDS. Despite the prevalence of this problem and its serious impact on the quality of life and therapy in HIV patients, the mechanisms by which alcohol abuse exacerbates HAART-induced neuropathic pain has not been investigated. To create a foundation for the rational design of new therapeutic strategies to treat alcohol-exacerbated neuropathic pain in HIV/AIDS patients, we propose to investigate the cellular mechanisms by which consumed alcohol aggravates antiretroviral-induced neuropathic pain. These studies will employ our well-established clinically relevant rodent models of HIV/AIDS therapy induced painful peripheral neuropathy, and neuropathic effects of alcohol abuse and withdrawal to create a foundation for the rational design of new mechanism-targeted strategies for the treatment and prevention of HAART induced neuropathic pain in patients who abuse alcohol. Our preliminary investigations clearly demonstrate that exposure to even moderate levels of alcohol in the diet dramatically increases the severity of antiretroviral-induced neuropathic pain. We propose to focus our investigation on the detailed analysis of the second messenger mechanisms and mitochondrial dysfunction in sensory neurons that underlie the effect of alcohol on antiretroviral-induced painful hyper-excitability of nerve fibers. In addition, because our preliminary investigations suggest that physiological stress pathways play a crucial role in the neurological effect of alcohol, we will also analyze the contributions of elements of these pathways. Our ultimate goal is that by improving the medical management of painful peripheral neuropathy in HIV/AIDS patients, this research will contribute to improving the quality of life, and the effectiveness of HAART therapy in HIV/AIDS patients. Public Health Relevance: The research that we propose to perform is designed to determine whether alcohol consumption affects the ability to treat patients with the most effective therapy available for AIDS, highly active antiretroviral therapy (HAART). With the development of HAART, AIDS has been converted from an often-fatal acute illness to a chronic disease. Unfortunately, HAART can cause nerve injury, producing severe pain as a side effect, which may require decreasing doses or even stopping this highly effective therapy. Since patients with AIDS are much more likely to use and abuse alcohol than individuals who do not have AIDS, and alcohol also has toxic effects on the peripheral nervous system, including painful peripheral neuropathy, the goal of this research proposal is to investigate how alcohol use exacerbates HAART-induced neuropathic pain in patients with AIDS. These studies will provide detailed information on how alcohol consumption can produce neuropathic pain in AIDS patients receiving HAART therapy. Our ultimate goal is to provide a foundation for the design of approaches to treat this threat to the quality of life of AIDS patients.